Processes and intermediates for quinine,quinidine,isomers and derivatives thereof

ABSTRACT

THE PREPARATION OF QUININE, QUINIDINE, ISOMERS AND DERIVATIVES THEREOF FROM THE CORRESPONDINGLY SUBSTITUTED 4METHYLQUINOLINE AND 1-ACYL(OR 1-H)-3-VINYL(OR LOWER ALKYL)-4- PIPERIDINE ACETIC ACID ESTERS (OR ACETALDEHYDE) THROUGH ALTERNATIVE SERIES OF REACTION STEPS WHICH COMPRISE CONDENSATION, HALOGENATION, DECAYLATION, REDUCTION, CYCLIZATION AND HYDROXYLATION, IS DESCRIBED. ALSO DESCRIBED IS THE PREPARATION OF 1-ACYL(OR 1-H)-3-VINYL-4PIPERIDINEACETIC ACIDS AND ESTERS THEREOF AND 1-ACYL-3VINYL-4-PIPERIDINEACETALDEHYDE UTILIZING THE CORRESPONDING 7-ACYLDECAHYDRO-2H-PYRIDO(3,4-D)AZEPIN-2-ONE, PREPARED FROM -2ACYL-1,3,4,7,8,8A-HEXAHYDRO-6(2H)-ISOQUINOLONE. THE END PRODUCTS ARE USEFUL AS ANTIMALARIAL AND ANTIARRHYTHMIC AGENTS.

United States Patent 3,772,302 PROCESSES ANDLNTERMEDIATES FOR QUININE, QUINIDINE, ISOMERS AND DERIVATIVES THEREOF Juerg Albert Walter Gutzwiller, Bettingen, Switzerland, v and Milan Radoje Uskokovic, Upper Montclair, N.J., assignors to Hotfmann-La Roche Inc., Nutley, NJ. No Drawing. Continuation-impart of application Ser. No.

104,784, Jan. 7, 1971, which is a continuation-in-part of application Ser. No. 837,354, June 27, 1969, which in turn is a continuation-in-part of application Ser. No. 741,914, July 2, 1968, all now abandoned. This application Dec. 27, 1971, Ser. No. 212,774

7 Int. Cl. C07d 43/24 US. Cl. 260-284 Claims ABSTRACT OF THE DISCLOSURE The preparation of quinine, quinidine, isomers and derivatives thereof from the correspondingly substituted 4- methylquinoline and 1-acyl( or 1-H)-3-vinyl(or lower alkyl)-4-piperidine acetic acid esters (or acetaldehyde) through alternative series of reaction steps which comprise condensation, halogenation, deacylation, reduction, cyclization and hydroxylation, is described. Also described is the preparation of l-acyl(or l-H)-3-vinyl-4- piperidineacetic acids and esters thereof and 1-acyl-3- vinyl-4-piperidineacetaldehyde utilizing the corresponding 7-acyldecahydro-2H-pyrido [3 ,4-d] aziepin-2one, prepared from 2 acyl-l,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end products are useful as antimalarial and antiarrhythmic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of application Ser. No. 104,784, filed Jan. 7, 1971, now abandoned, which is a continuation-in-part of application Ser. No. 837,354, filed June 27, 1969, now abandoned, which in turn is a continuation-impart of Ser. No. 741,914, filed July 2, 1968, now abandoned.

BRIEF SUMMARY OF THE INVENTION The invention relates to a process for preparing quinine, quinidine, isomers and derivatives thereof which comprises:

(a) Condensing the correspondingly substituted 4- rnethylquinoline with racemic or optically active cis or trans 1-acyl(or l-H)-3-vinyl(or lower alkyl)-4-piperidine acetic acid ester to yield the corresponding racemic or optically active cis or trans 4-{3-[l-acyl(or l'H)-3-vinyl (or lower alkyl)-4-piperidyl] -2-oxo-propyl}quinoline;

(b) Deacylating, if necessary, and reducing the product of step (a) to yield the corresponding racemic or optically active epimeric 4{cis or trans-3-[3-vinyl(0r lower alkyl) 4 piperidyl]-2&hydroxypropyl}quinolines. If desired, this reaction product can be acylated to yield racemic or optically active epimeric 4-{cis 0r trans-3-[3-vinyl (or lower alkyl)-4-piperidyl1-25-acyloxypropyl}quinolines or dehydrated to yield racemic or optically active Cis or Patented Nov. 13, 1973 ice trans 4-{cis or trans 3-[3-vinyl(or lower alkyl)-4- piperidyl] prop-1-enyl}quinolines;

(c) An alternate process comprises condensing the correspondingly substituted 4-methylquinoline with racemic or optically active cis or trans 1-acyl-3vinyl(or lower alkyl)-4-piperidineacetaldehyde to yield the corresponding racemic or optically active epimeric 4'{cis or trans-3-[1- acyl3vinyl (or lower alkyl -4-piperidyl] -2.f-hydroxypro pyl}quinolines, and deacylating, this reaction product to yield the corresponding racemic or optically active epimeric 4-{cis or trans-3-[3-vinyl(or lower alkyl)-4-piperidyl]-2-hydroxypropyl}quinolines;

(d) Cyclizing the hydroxy, acyloxy or prop-l-enyl quinoline product of step (b) or (c) to yield the corresponding racemic or optically active 4{a-[5-vinyl(or lower alkyl)-2-quinuclidinyl]-methyl}quinoline, epi-meric in positions 2 and 5;

(e) Hydroxylating the product. of step (d) to yield the corresponding racemic or optically active a-[5-vinyl(or lower alkyl)-2-quinuclidinyl] 4 quinolinemethanol, epimeric in positions on, 2 and 5; and

(f) Recovering the desired reaction product.

An alternate process comprises:

(g) Halogenating the product of step (a) above to yield the corresponding racemic or optically active epimeric 4-{cis or trans 3-[l-acyl-3-vinyl(or lower alkyl)-4- piperidyl]-1.f-halo-Z-oxopropyl}quinolines;

(h) Reducing the product of step (g) with subsequent cyclization to yield a mixture of the corresponding racemic or optically active epimeric 4-{cis or trans'3-[1-acyl- 3-vinyl(or lower alkyl) 4 piperidyl]-l,2{-oxapropyl] quinolines;

(i) Deacylating the product of step (g) to yield a mixture of the corresponding racemic or optically active epimeric 4-{cis or trans 3-[3-vinyltor lower alkyl)-4-piperidyl]-l.,2-oxapropyl}quinolines;

(j) Cyclizing the product of step (h) to yield the corresponding racemic or optically active a-[5-vinyl(or lower alkyl)-2-quinuclidiny1]-4-quinolinernethanol, epimeric in positions a, 2 and 5; and

(k) Recovering the desired reaction product.

The end products are useful as antimalarial and antiarrhythmic agents.

In another aspect, the invention relates to a process for preparing racemic or optically active cis or trans 1-acyl(or 1-H)-3-vinyl 4 piperidineacetic acid and esters thereof and racemic or optically active cis or trans 1-acyl-3-vinyl 4-piperidineacetaldehyde by:

(a) Nitrosating a racemic or optically active cis or trans 7 acyl-decahydro-2H-pyrido[3,4-d1azepin-2-one to yield the corresponding racemic or optically active cis or trans 7-acyl-l-nitroso-decahydro-2H-pyrido 3,4-d] azepin- 2-one;

(b) Pyrrolyzing the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans l-acyl-3-vinyl-4-piperidineacetic acid; and

(c) Hydrolyzing, if desired, and esterifying the reaction product of step (b) to yield the corresponding racemic or optically active cis or trans l-acyl(or 1-H)-3-vinvl- 4-piperidineacetic acid ester; and

(d) Reducing and acylating the reaction product of step (c) to yield racemic or optically active cis or trans 1-acy1-3-vinyl-4-piperidineacetaldehyde.

In a further aspect, the invention relates to an alternate process for preparing racemic or optitcally active cis and 4 6(2H)-isoquinolone to the corresponding racemic or optically active 2-acyl-1,2,3,4,7,8,9,9a-octahydro-6H-pyrido [3,4d]azepin-6-one; and

(b) Hydrogenating the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans yK y -p p acld and trans 7-acyl-decahydro-2H-pyrido[3,4-d]azepin-2-one. esters thereof by: In yet another aspect, the invention relates to novel (a) Alcoholizing a racemic or optically active cis or compounds trans 7-acyl-decahydro-ZH-pyrido[3,4-d]azepin-2one to yield the corresponding racemic or optically active cis or 10 DETAILED DESCRIPION OF THE INVENTION trans 1-acyl-3-(2-aminoethyl) 4 piperidineacetic acid The term lower alkyl as used herein denotes a hyesters; drocarbon group containing 1-7 carbon atoms, such as (b) Methylating the reaction product of step (a) to methyl, ethyl, propyl, butyl and the like; methyl and yield the corresponding racemic or optically active cis or ethyl are preferred. The term lower alkoxy" denotes a trans l-acyl-3-(Z-dimethylaminoethyl)-4-piperidineacetic lower alkyl ether group in which the lower alkyl moiety acid esters; is described as above, such as methoxy, ethoxy, propoxy, (c) Oxidizing the reaction product of step (b) to yield butoxy and the like; methoxy and ethoxy are preferred. the corresponding racemic or optically active cis or trans The term halogen" denotes all of the halogens, i.e., 1-acyl-3-(2 dimethylaminoethyl)-4piperidineacetic acid bromine, chlorine, fluorine and iodine. Preferred are ester N-oxide; and chlorine and bromine. The term acyl denotes lower (d) Pyrolyzing the reaction product of step (c) to alkanoyl of 14 carbon atoms such as formyl, acetyl, yield the desired acetic acid and esters thereof. propanoyl, butanoyl, heptanoyl, and the like; ar-lower In still another aspect, the invention relates to a process alkanoyl, preferably phenyl-lower alkanoyl wherein for preparing racemic or optically active cis or trans 7- phenyl may be substituted by one or more lower alkyl, Y Y -PI P 2 one whim lower alkoxy or halogen groups such as benzoyl and the comprises: like. The term aryl" means phenyl which may be sub- (a) Hydrogenatmg a racemlc optlfiauy stituted by one or more lower alkyl, lower alkoxy or acyl-1,3,4,7,8,8a-hexahydro-6(2H) isoqumolone to yield halogen groups. The term uaralkyln means a hydrocarg z fi zfsg gsg gig g zigfi ggg ii ms or trans bon group of 7-12 carbon atoms such as benzyl, phen- (b) Converting the reaction product of step (a), ethyl PhenYlPmPYl e. The term acylox y through a Schmidt Rearrangement, to the corresponding means an acyloxy wherein the acyl moiety is as hereinracemic or optically active cis or trans 7-acyl-decahydrobefore descnbed' for example lower alkanoyloxy and 2H-pyrido[3,4-d]azepin-2 one. alkanoyloxy' Alternatively, by a process which comprises: The Proccss for Prcparlng quFlme, qmmdme, isomers (a) Converting, through a Schmidt Rearrangement, a and derivatives thereof is exemplified by Reaction Scheme racemic or optically active 2-acyl-l,3,4,7,8,8a-hexahydro- Ia, Ia, Ia", Ib, Ib' and lb".

Scheme Ia CH; {1) (now wherein m is 0, 1 or 2; R is hydrogen, hydroxy, halogen, trifiuoromethyl, lower alkyl, lower alkoxy, or when m is 2, R taken together with an adjacent R is also methylenedioxy; R is vinyl or lower alkyl, preferably ethyl; R is hydrogen or lower alkyl; R, is hydrogen or acyl; and R is lower alkyl, aryl or ar-lower alkyl. As is evident from the above when m is 2, R or the like is individually selected from the various groupings hereinbefore described.

Compounds of the Formula 121 and Ha above are useful as antimalarial and antiarrhythmic agents.

In Reaction Scheme Ia, 4-methyl-quinolines of Formula X, which are known compounds or are analogs of known compounds readily obtained by known procedures, are condensed with l-acyl (or 1-H)-3(R)-vinyl(or lower alkyl)-4(S)-piperidineacetic acid ester of Formula IXa, antipode or its racemate which are known compounds, are analogs of known compounds readily obtained by known procedures, or are prepared as hereinafter described, in the presence of a base, for example, sodium hydride, an alkali metal alkoxide such as sodium methoxide, or lithium dialkylamide such as lithium diisopropylamide to yield 4{3-[ l-acyl(or 1-H)3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-oxopropyl}quinoline of Formula VIIIa, antipode or its racemate. The condensation is suitably carried out at room temperature; however, temperatures above or below room temperature may be employed. Preferably, the condensation is conducted at a temperature within the range of about 70 and about 50 C. Moreover, the condensation can be suitably carried out in the presence of an inert organic solvent, for example, a hydrocarbon, such as benzene, hexane and the like, or an ether such as ether, tetrahydrofuran or dioxane, or dimethylformamide or hexamethylphosphoramide.

The 4-{3-[l-acyl(or l-H)-3(R)-vinyl(or lower alkyl) 4(S)-piperidyl]-2-oxopropyl}quinoline of Formula VIIIa, antipode or its racemate is converted to the mixture of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S)-piper- 6 idyl]-2-hydroxypropyl}quinolines of Formula VIa, their antipodes or racemates by simultaneous deacylation, if necessary, and reduction. The deacylation and reduction are conveniently etfected utilizing a reducing agent, for example, diisobutylaluminum hydride, sodium aluminum hydride and the like, in an inert organic solvent, for example, a hydrocarbon such as benzene or toluene, ether, tetrahydrofuran and the like. The deacylation and reduction are suitably carried out at room temperature or below, preferably, at a temperature within the range of about --70 to about 25 C. The reduction and deacylation can also be carried out stepwise, i.e., by first reducing a compound of Formula VIIIa, wherein R is acyl, with sodium borohydride, followed by deacylation utilizing, for example, aqueous hydrochloric or sulfuric acid as the deacylating agent. If desired, the compound of Formula VIa can be esterified to the corresponding mixture of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S)- piperidyl]-2&acyloxypropyl}quinolines of Formula VIIa, their antipodes or racemates utilizing known procedures, for example, reaction with the corresponding organic acid in the presence of a catalyst, such as boron trifiuoride. Alternatively, if desired, the compound of Formula VIa can be converted to cis and trans 4-{3-[3(R)-vinyl(or lower alkyl)-4(R)-piperidyl]-prop 1 enyl}quinolines of Formula Va, their antipodes or racemates utilizing a dehydrating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like, in the presence of an organic base, for example, a tertiary amine such as pyridine, triethylamine and the like, at a temperature within the range of about 0 to about room tempera ture.

The cyclization of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S)-piperidyl] 2g hydroxy(or acyloxy)propyl} quinolines of Formulas VIa and VI Ia, their antipodes or racemates, respectively and cis and trans 4-{3-[3(R)-vinyl (or lower alkyl)-4(R)-piperidyl]prop-l-enyl}quinolines of Formula Va, their antipodes or racemates to 4-{a-[5(R)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S) and 2(R)- yl]-methyl}quinolines of Formulas Illa and IVa, their antipodes or its racemate is carried out utilizing a cyclizing agent, for example, an organic acid, such as glacial acetic acid or the like. The cyclization is suitably carried out at room temperature; however, temperatures above or below room temperature may also be employed. It is preferred to employ a temperature within the range of about 25 to about C. Moreover, the cyclization can beconveniently conducted in the presence of an inert organic solvent, for example, a hydrocarbon such as benzene or toluene, or an ether, such as diethyl ether or tetrahydrofuran.

The hydroxylation of the compounds of Formulas IIIa and IVa or their racemates to a(R)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl] 4 quinolinemethanol of Formula Ia, its antipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)- yl]-4quinolinemethanol of Formula Ila, its antipode or racernate, respectively, is carried out, for example, in the presence of molecular oxygen and a reducing agent, such as dimethylsulfoxide, pyridine, triphenylphosphine, platinum black, or a trialkylphosphite, such as triethylphosphite, or the like, in a strongly basic solution.

A suitable base for the reaction described above comprises, for example, an alkali metal alkoxide, such as potassium t-butoxide, sodium t-butoxide, sodium isoamylate, sodium methoxide or the like, or an alkali metal amide, such as lithium diisopropylamide, sodium amide or the like. Conveniently, a solvent such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, pyridine, t-butanol, a hydrocarbon such as benzene or toluene, an ether such as tetrahydrofuran, dioxane or the like, or mixtures thereof can be utilized. A preferred reaction medium comprises a mixture of dimethylsulfoxide and tbutanol in the presence of potassium t-butoxide.

Scheme Ia I R: I JH XXIIIa 1)m l J XXIVa VIa wherein R R and m are previously described and R',,

is acyl.

In Reaction Scheme Ia' an alternative process for the preparation of compounds of Formula VIa is described. 4-methylquinolines of Formula X are condensed with 1-acyl-3 (R)-vinyl- (or lower alkyl)-4(S)-piperidineacetaldehyde of Formula XXIIIa, its antipode or racemate which are new compounds and are prepared as hereinafter described, in the presence of base, for example, sodium hydride, an alkali metal alkoxide such as sodium methoxide, or lithium dialkylamide such as lithium diisopropylamide to yield the mixture of epimeric 4-{3-[1- acyl-3(R)-vinyl- (or lower alkyl)-4(S)-piperidyl]-2-hydroxypropyl}quinolines of Formula XXIVa, their antipodes of racemates. The compounds of Formula XXIVa are deacylated to the corresponding mixture of epimeric 4-{3-[3(R)-vinyl (or lower alkyl)-4(S)-piperidyl]-2-hydroxypropyl}quinolines of Formula VIa, their antipodes or racemates, utilizing a deacylating agent, for example, alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, a reductive deacylating agent such as lithium aluminum hydride, sodium aluminum hydride, diisobutyl aluminum hydride and the like. Preferably, the deacylation is suitably carried out at room temperature; however, temperatures above and below room temperature may be employed. Moreover, the deacylation can be suitably carried out in the presence of an inert organic solvent, for example, a lower alkanol, such as methanol or ethanol, or an ether, such as tetrahydrofuran or 'dioxane.

8 Scheme Ia e... l; 0 "(J x--| o (Ram (Rom N VIIIa n XXa 05/ H a? H I 0m I 7 \N/ XXla \N/ XXIIa H Unb (Ring j N in N lla wherein R R;;, R, and m are as previously described ::'and X is halogen.

In Reaction Scheme Ia", an alternative process for the conversion of compounds of Formula VIIIa to the com pounds of Formulas Ia and IIa is described. The conversion of the 4-{3-[l-acyl-3(R)-vinyl (or lower alkyl)- 4(S)-piperidyl]-2-oxopropyl}quinoline of Formula VIIIa', its antipode or racemate to the corresponding mixture of epimeric 4-{3-[1-acyl-3(R)-vinyl (or lower alkyl)-4(S)- piperidyl]-1halo-2-oxopropyl}quinolines of Formula XXa, their antipodes or racemates, respectively, is cffected utilizing a halogenating agent such as N-bromosuccinimide, N-chloro-succinimide, -N-bromoacetamide and the like. The halogenation can be conducted in an inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a halogenated hydrocarbon such as carbon tetrachloride; an ether such as diethylether, tetrahydrofuran, dioxane and the like. Conveniently, the reaction can be initiated by a freeradical catalyst such as dibenzoylperoxide or by irradiation with infrared. The temperature is not critical, however; it is preferred to conduct the reaction at a temperature in the range of about room temperature and the reflux temperature of the reaction mixture.

The conversion of the epimeric compounds of Formula XXa, their antipodes or racemates to the corresponding mixture of diastereomeric 4-{3-[l-acyl-3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-5,2-oxapropyl}quinolines of the Formula )Ofla, their antipodes or racemates can be effected utilizing a reducing agent, for example, alkali metal hydrides such as sodium borohydride, potassium borohydride, lithium tritertiarybutoxyaluminum hydride and the like. The reduction is conveniently effected in an inert organic solvent, for example, aliphatic alcohols such as methanol, ethanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like, at a temperature in the range of about 70 C. and about the reflux temperature of the reaction mixture.

The conversion of the compound of Formula XXIa to the corresponding mixture of the diastereomeric 4-{3- [3(R)-vinyl(or lower alkyl)-4(S)piperidyl]-1,2-oxopropyl}quinolines of the Formula XXIIa, their antipodes or racemeates is effected using a deacylating agent, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxides, or a reducing deacylating agent, for example, dialkylaluminum hydride such as diisobutylaluminum hydride, or an alkali metal aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride and the like. The deacylation is conveniently conducted in the presence of an inert organic solvent, for example, lower alkanols such as methanol, ethanol and the like, hydrocarbons such as toluene and the like, ethers such Scheme 1b I COORI (Rl)m@ H\ X IXb H l T Etc-on,

10 as diethylether, tetrahydrofuran and the like. The deacylation temperature is not critical. Conveniently, it may be in the range of about -70 C. to about the reflux temperature of the reaction mixture.

The conversion of the compounds of Formula XXIIa to the corresponding mixture comprising a(R)-[5(R)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4-quino linemethanol of Formula Ia, its antipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl) 4 (S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol of Formula Ila, its antipode or racemate is effected by reaction with a weak organic or inorganic protonic acid, for example, water, ammonium chloride, lower alkanols such as methanol, ethanol and the like, Lewis acids such as aluminum oxide, aluminum chloride, boron trifluoride and the like. Conveniently, conversion is conducted in the presence of an inert organic solvent, for example, carbon disulfide, hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as dichloromethane, carbontetrachloride, chloroform and the like, and ethers such as diethylether, tetrahydrofuran, dioxane and the like. The temperature of the reaction is not critical. Conveniently, it may be in the range of about 0 C. and about the reflux temperature of the reaction mixture.

wherein R R R R R and m are as previously described.

'I-he hereinafter described reaction steps of Reaction Scheme Ib are effected utilizing the procedures and conditions set forth in Scheme Ia. The 4-methyl-quinoline of Formula X is condensed with l-acyl (or 1-H)-3(S)-vinyl (or lower alkyl)-4(S)-piperidineacetic acid ester of Formula IXb, its antipode or racemate to yield 4-{3-[l-acyl (or 1-H)-3(S)-vinyl(or lower alkyl)-4(S)-piperidyl]-2- oxopropyl}quinoline of Formula VIIIb, its antipode or racemate. The compound of Formula VIIIb is deacylated, if necessary, and reduced to the mixture of epimeric 4- {3-[3(S)-vinyl(or lower alkyl) 4(S)-piperidyl]-2-hydroxypropyl}quinolines of Formula VIb, their antipodes or racemates. If desired, the compounds of Formula VIb can be esterified to the mixture of epimeric 4-{3-[3(S)- vinyl(or lower alkyl) 4(S)-piperidyl]-2-acyloxypropyl} quinolines of Formula VIIb, their antipodes or racemates or, alternatively, it can be converted to cis and trans 4-{3-[3(S)-vinyl(or lower alkyl)-4(R)-piperidyl]-prop-lenyl}quinolines of Formula Vb, their antipodes or racemates. The compounds of Formula Vb, VIb or VIIb are cyclized to 4-{a-[5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S) and 2(R)-yl]-rnethyl}quinolines of Formulas IlIb and IVb, their antipodes or racemates. The com pounds of Formulas IIIb and Nb are hydroxylated to a(R)-[5 (S)-vinyl(or lower alkyl) 4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol of Formula Ib, its antipode or racemate and aS)-[5(S)-vinyl(or lower alkyl)-4(S)- quinuclidin 2(R)-yl]-4-quinolinemethanol of Formula IIc, its antipode or racemate, respectively.

wherein R R R'., and m as previously described.

The hereinafter described reaction steps of Reaction Scheme Ib are effected utilizing the procedures and conditions set forth in Scheme Ia. 4-Methyl-quinolines of Formula X are condensed with l-acyl-3 (S)-vinyl(or lower alkyl)-4(S)-piperidineacetaldehyde of Formula XXIHb, its antipode or racemate which are new compounds and are prepared as hereinafter described, to yield the mixture of epimeric 4-{3-[1-acyl-3(S)-vinyl(or lower alkyl)-4(S)- piperidyl] 2g hydroxypropyl}quinolines of Formula XXIVb, their antipodes or racemates. The compounds of Formula XXIVb are deacylated to the corresponding mixture of epimeric 4-{3-[3 (S)-vinyl(or lower alkyl)-4(S)- piperidyl]-2-hydroxypropyl}quinolines of Formula VIb, their antipodes or racemates.

The hydroxylation of the compound of Formulas IIIa,b-IVa,b to the end products of Formulas Ia,b-IIa,b, 1.e.,

can also be effected utilizing molecular oxygen and a catalyst such as platinum, tris(triphenylphosphine) rhodium chloride or the like or by oxidation utilizing a compound such as selenium dioxide, ruthenium tetroxide, palladium acetate, mercuric acetate, thallium triacetate, manganese dioxide, cerium (IV) oxide, or the like.

Alternate procedure for the conversion of the compounds of Formula VIa,b to the corresponding compound of Formula IIIa,bIVa,b are exemplified in Reaction Scheme V.

0 r RKH 10 0 [E Chm H (Ron:

\N XXXI l vnu o N can 3:;

o-so cm \N xXXIr rmm (it) xXXnr The conversions of Compounds VIa,b to the corresponding compounds of Formula XXXI is effected utilizing a chloroformate such as benzylchloroformate. The compounds of Formula XXXI are converted to the compounds of Formula XXXII by tosylation with a compound such as p-tolueuesulfonylchloride or p-toluenesulfonic acid anhydride in a solvent such as pyridine. The conversion of the compounds of Formula XXXII to the corresponding compound of Formula XXXlll is effected by the removal of the N-carbobenzoxy group utilizing, for example, acetic acid/hydrogen bromide mixture. The c'yclization of the compounds of Formula XXXIII to the corresponding compound of Formula IIIa,b-IVa,b is effected by heating in an organic solvent such as methanol, ethanol, dimethylformamide, dimethylsulfoxide and the like.

llb

wherein R R R}, m and X are as previously described.

In Reaction Scheme Ib", an alternative process for the conversion of compounds of Formula VIIIb to the compounds of Formulas Ib and Ilb is desired. The conversion of the 4 {3-[1-acyl-3(S)-vinyl (or lower alkyl)-4(S)- piperidyl]-2-oxopropyl}quinoline of Formula VIlIb', its antipode or racemate to the corresponding mixture of epimeric 4-{3-[l-acyl-3(S)-vinyl (or lower alkyl)-4(S)- piperidyl] 1g-halo-2-oxopropyl}quinolines of Formula XXb, their antipodes or racemates, respectively, is effected utilizing a halogenating agent such as N-bromo-succinimide, N-chloro-succinimide, N-brornoacetamide and the like. The halogenation can be conducted in an inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a halogenated hydrocarbon such as carbon tetrachloride; an ether such as diethylether, tetrahydrofuran, dioxane and the like. Conveniently, the reaction can be initiated by a free radical catalyst such as dibenzoylperoxide or by irradiation with infrared. The temperature is not critical, however, it is preferred to conduct the reaction at a temperature in the range of about room temperature and the reflux temperature of the reaction mixture.

The conversion of the epimeric compounds of Formula XXb, their antipodes or racemates to the corresponding mixture of diastereomeric 4 {3-[l-acyl-3(S)-vinyl (or lower alkyl) 4(S)-piperidyl]-l5,2-oxapropyl}quinolines of the Formula XXIb, their antipodes or racemates can be effected utilizing a reducing agent, for example, alkali metal hydrides such as sodium borohydride, potassium borohydride, lithium tritertiarybutoxyaluminum hydride and the like. The reduction is conveniently effected in an inert organic solvent, for example, aliphatic alcohols such as methanol, ethanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like, at a temperature in the range of about 70 C. and about the reflux temperature of the reaction mixture.

The conversion of the compound of Formula XXIb to the corresponding mixture of the diastereomeric 4-{3- [3(S) vinyl(or lower alkyl)-4(S)-piperidyl]-l5,25-oxapropyl}quinolines of the Formula XXlIb, their antipodes or racemates is effected using a deacylating agent, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxide, or a reducing deacylating agent, for example, dialkylaluminum hydride such as diisobutylaluminum hydride, or an alkali metal aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride and the like. The deacylation is conveniently conducted in the presence of an inert organic solvent, for example, lower alkanols such as methanol, ethanol and the like, hydrocarbons such as toluene and the like, ethers such as diethylether, tetrahydrofuran and the like. The deacylation temperature is not critical. Conveniently, it may be in the range of about 70 C. to about the reflux temperature of the reaction mixture.

The conversion of the compounds of Formula XXIIb to the corresponding mixture comprising a(R)-[5(S)-vinyl- (or lower alkyl) 4(S) quinuclidin-2(S)-yl]-4-quinolinemethanol of Formula Ib, its antipode or racemate and (1(5) [5(5) vinyl(or lower alkyl)-4(S)-quinuclidin 2(R)yl]-4-quinolinemethanol of Formula llb, its antipode or racemate is effected by reaction with a weak organic or inorganic protonic acid, for example, water, ammonium chloride, lower alkanols such as methanol, ethanol and the like, Lewis acids such as aluminum oxide, aluminum chloride, boron trifiuoride and the like. Conveniently, conversion is conducted in the presence of an inert organic solvent, for example, carbo disulfide, hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as dichloromethane,'carbontetrachloride, chloroform and the like, and ethers such as diethylether, tetrahydrofuran, dioxane and the like. The temperature of the reaction is not critical. Conveniently, it may be in the range of about 0 C. and about the reflux temperature of the reaction mixture.

The various other process aspects of the-invention are exemplified by the following reaction schemes Ila, Ilb, llIa, Illb and 1V.

Scheme lla wherein R and R are as previously described, and R is lower alkyl, aryl or ar-lower alkyl.

In Reaction Scheme Ila, the conversion of 7-acyl-decahydro 2H pyrido[3(R),4(S) d]azepin-2-one of Formula XIa, its antipode or racemate to 7-acyl-l-nitrosodecahydro 2H pyrido[3(R),4(S)-d]-azepin-2-one of Formula XIla, its antipode or racemate, respectively, is carried out utilizing a nitrosetting agent, such as, for example, sodium nitrite or dinitrogen tetroxide. Conveniently, the reaction can be conducted in the presence of a solvent, for example, an organic acid such as acetic acid, or a chlorinated hydrocarbon such as carbon tetrachlo ride. The nitrosation is conveniently conducted at a tem perature within the range of about 0 C. to about room temperature, preferably at 0 C.

The compound of Formula Xlla is converted to l-acyl- 3(R)-vinyl-4(S)-piperidineacctic acid of: Formula Xllla, its antipode or racemate, respectively, by pyrolysis. Conveniently, the pyrolysis is conducted at a temperature with in the range of about room temperature to abo t 200 C 17 preferably at a temperature within the range of about 100 C. to about 130 C. Conveniently, a high boiling solvent such as xylene, decaline and the like, can be utilized in the reaction.

The compound of Formula XIIIa is converted to 1- acyl(orl-H)-3(R)-vinyl-4(S)-piperidineacetic acid ester of Formula lXc, its antipode or racemate, respectively, utilizing an esterir'ying agent, for example, a lower alkanol, such as methanol, ethanol, propanol and the like in the presence of, for example, an inorganic acid such as hydrochloric acid, sulfuric acid and the like. When R is hydrogen, however, the esterification is preceded by hydrolysis in the presence of, for example, an aqueous inorganic acid, such as hydrochloric acid, sulfuric acid and the like.

Compounds of Formula Xla, wherein R is alkyl, for instance, ethyl, can be prepared as described in Scheme IV.

Scheme IIb IXd wherein R R and R are as previously described.

In a like manner, in Reaction Scheme IIb, the conversion of 7-acyl-decahydro 2H pyrid[3(S),4(S) d] azepin-Z-one of Formula XIb, its antipode or racemate to 7-acyl-1-nitroso-decahydro 2H pyrido[3(S),4(S) d] azepin-2-one of Formula XIIb, its antipode or racemate, respectively, is carried out. The compound of Formula Xllb is converted to l-acyl-3(S)-vinyl-4(S) piperidineacetic acid of Formula XIIIb, its antipode or racemate, respectively, by pyrolysis. The compound of Formula XIIIb is converted to l-acyl(or 1-H)-3(S)-vinyl 4(8)- piperidineacetic acid ester of Formula IXd, its antipode or racemate, respectively.

SC IIEME llla l COOR:

XIVa

COOR;

wherein R R and R are as previously described.

In Reaction Scheme 11121, 7 acyl decahydro 2H- pyrido[3(R),4(S) dlazepin 2 one of Formula XIa, its antipode or racemate is converted to 1 acyl 3(R)- (2 aminoethyl) 4(5) piperidineacetic acid ester of Formula XIVa, its antipode or racemate, respectively, utilizing an alcoholizing agent, for example, a lower alkanol such as methanol, ethanol, propanol and the like, in the presence of, for example, anhydrous inorganic acid such as hydrochloric acid, sulfuric acid and the like. Conveniently, the alcoholysis is conducted at a temperature within the range of about room temperature to about the boiling point of the alkanol.

The compound of Formula XIVa is converted to l-acyl- 3 (R) -(2-dimethylaminoethyl -4-(S -piperidineacetic acid ester of Formula XVa, its antipode or racemate, respec tively, utilizing a methylating agent such as, for example, formic acid/formaldehyde mixture or formaldehyde/ Raney nickel. The N-methylation is conveniently conducted at a temperature within the range of about room temperature to about the boiling point of the methylating agent.

The compound of Formula XV a is converted to l-acyl- 3(R)-(Z-dimethylaminoethyl)4(S) piperidinacetic acid ester N-oxide of Formula XVIa, its antipode or racemate, respectively, utilizing an oxidizing agent, for example, hydrogen peroxide or a perorganic acid such as, peracetic acid. The oxidation is conveniently conducted in the presence of a solvent, for example, lower alkanol, such as methanol, ethanol, propanol and the like, or a hydrocarbon such as benzene and the like. The oxidation is conveniently conducted at a temperature within the range of about 0 to about room temperature, preferably at 0 C.

The compound of Formula XVIa is converted to l-acyl (or l-H)-3(R)-vinyl 4(5) piperidineacetic acid ester of Formula IXc, its antipode or racemate, respectively, by pyrolysis. Such pyrolysis is conveniently conducted at a temperature in the range of about to about 200 C., preferably at a temperature within the range of about to about C. When R is hydrogen, however, the pyrolysis is followed by hydrolysis and reesterification.

19 SCHEME IlIb COOR;

R; XIVb COOR: COOR:

1 R IX wherein R R and R are as previously described.

In a like manner, in Reaction Scheme IIIb, 7-acyl-decahydro-2H-pyrid0[3(S),4(S)-d]azepin-2-one of Formula Xlb, its antipode or racemate is converted to 1-acyl-3(S) (2-aminoethyl)-4(S)-piperidineacetic acid ester of Formula XIVb, its antipode or racemate, respectively. The compound of Formula XIVb is converted to 1-acyl-3(S)- (Z-dimethylaminoethyl)-4(S)-piperidineacetic acid ester of Formula XVb, its antipode or racemate, respectively. The compound of Formula XVb is converted to l-acyl- 3(S)-(Z-dimethylaminoethyl)-4(S)-piperidineacetic acid ester N-oxide of Formula XVIb, its antipode or racemate, respectively. The compound of Formula XVIb is converted to l-acyl(or 1-H)-3 (S)-vinyl-4(S)-piperidineacetic acid ester of Formula IXd, its antipode or racemate.

SCHEME IV X VIIIa wherein R is as previously described.

In the Reaction Scheme IV, racemic 2-acetyl-l,3,4,7,8, 8a-hexahydro-6(2H)-isoquinolone of Formula XVII is converted to the racemic cis and trans 2-acyl-octahydro- 6(2H)-isoquinolones of Formula XVIIIa and XVIIIb, respectively, utilizing a hydrogenating agent, for example, hydrogen in the presence of palladium or rhodium catalyst. Conveniently, the hydrogenation can be conducted in the presence of a solvent, for example, a lower alkanol such as methanol, ethanol, propanol and the like, with or without an inorganic acid such as hydrochalic acid, for example, hydrochloric acid and the like. The hydrogenation can be conveniently conducted at a temperature within the range of about room temperature and about 50 C.

The racemates of the compounds of Formula XVIIIa or XVIIIb are resolved to the corresponding optical antipodes by conventional methods which are further illustrated by Examples 3, 4, 5.

The conversion of 2-acyl-4a(S),8a(R)-octahydro- 6(2H)-isoquinolone of Formula XVIIa, its antipode or racemate to 7-acyldecahydro-2H-pyrido[3(R),4(S)-d] azepin-2-one of Formula XIa, its antipode or racemate, respectively, is carried out utilizing the known Schmidt rearrangement, i.c., the reaction of the compound of Formula XVIIIa with sodium azide in the presence of an inorganic acid such as sulfuric acid or polyphosphoric acid, with or without solvent, at a temperature within the range of from about 0 to about C.

In a like maner, 2-acetyl-4a(S) ,8a(S)-octahydro-6(2H)- isoquinolone of Formula XVIIIb, its antipode or racemate is converted to 7-acyl-decahydro-2H-pyrido[3(S),4(S)d] azepin-Z-one of Formula Xlb, its antipode or racemate, respectively.

The racemic compound of Formula XVII is converted to the racemic 2-acyl-l,2,3,4,7,8,9,9a octahydro 6H- pyrido[3,4-d]azepin-6-one of Formula XIX utilizing the Schmidt rearrangement as hereinbefore described. The compound of Formula XIX is converted to the racemic compound of Formula XIa utilizing a hydrogenating agent such as hydrogen in the presence of a catalyst, such as rhodium or palladium, in a solvent, for example, an alkanol, such as ethanol, methanol and the like, in the presence of an inorganic acid, such as hydrochloric acid.

In another aspect, the invention relates to the compounds of Formulas Ib, IIb, IIIb, lVb, Va, Vb, VIa, Vlb, VIIa, VIIb, VIIIa, VIlIb, IXb, XIa, Xlb, XIIa, Xllb, XIIIb, XIVa, XIVb, XVa, XVb, XVIa, XVIb and XIX.

The compounds of Formulas Ib and 11b are useful IIIc IVc wherein n is to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, halogen, or when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is C C', alkoxy, lower alkyl, trifiuoromethyl or halogen; when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydroxy, hydrogen, trifluoromethyl, halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen, and their antipodes and racemates.

Also included in the purview of the invention are compounds of the formulas 01130 i CHJO w and IVd

Il'Id wherein R is methyl or C -C lower alkyl, their antipodes and racemates.

Compounds of Formulas IIIc, IIId, We and IVd are useful intermediates.

In still another aspect, the invention relates to compounds of the formulas IIIe IVe wherein n is 0 to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifiuoromethyl, halogen, or when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is C2-C7 alkoxy, lower alkyl, trifluoro methyl or halogen; when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl, halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen and their antipodes and racemates.

As is evident from the above R or R or the like are individually selected from the various groupings hereinbefore described. Moreover, when m or n is 2, R or R or the like can additionally form with an adjacent R or R or the like the methylenedioxy radical. Thus, either when m or n is 1 or 2, R or R or the like can individually also represent hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl. Additionally, when m or n is 2, two adjacent groupings of R or R can together represent methylenedioxy.

In yet another aspect, the invention relates to compounds of the formulas 1R" @P N I'i CHaO CHaO and III: IVI

wherein R is methyl or C -C lower alkyl, their antipodes and racemates.

Compounds of Formulas IIIe, IIIf, IVe and IV f are useful intermediates.

In a further aspect, the invention relates to compounds of the formulas wherein n is 0 to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifiuoromethyl or halogen, and when n is 2, R11, taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is C -C alkoxy, lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl or halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen, and their antipodes and racemates,

and pharmaceutictlly acceptable acid addition salts.

Exemplary of the compounds of Formulas Ic and He are:

6,8-dimethoXy-a(R) [5 (S) ethyl 4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6',8'-dirnethoxy-3-epi-dihydrocinchonidir1e] its antipode and racemic analog;

7 chloro a(R) [5(S) ethyl 4(S) quinuclidin 2(8)-yl]-4-quinolinemethanol [hereinafter referred to as 7'-chloro-3-epi-dihydrocinchonidine] its antipode and racemic analog;

6,7 methylenedioxy ot(R) '[5(S) ethyl 4(8)- quinuclidin-2(S)-yl] 4 quinolinemethanol [hereinafter referred to as 6,7'-methylenedioxy-3-epi-dihydrocinchonidine] its antipode and racemic analog;

7 trifiuoromethyl @(R) [5(5) ethyl 4(S)-quinuclidin-Z (S -yl] -4-quinolinemethanol [hereinafter referred to as 7'-trifiuoromethyl 3 epi-dihydrocinchonidine] its antipode and racemic analog;

6,8 dimethoxy @(S) [5(5) ethyl 4(S) quinuclidin 2(R) yl] 4 quinolinemethanol hereinafter re- 23 ferred to as 6',8'-dimethoxy-3-epi-dihydrocinchonine] its antipode and racemic analog;

7 chloro a(S) [(S) ethyl 4(S) quinuclidin- 2(R)-yl]4-quinolinemethanol [hereinafter referred to as 7'-chloro-3-epidihydrocinchonine] its antipode and racemic analog;

6,7 methylenedioxy @(S) [5(5) ethyl 4(S)- quinuclidin-2(R)-yl] 4 quinolinemethanol [hereinafter referred to as 6',7-methylenedioxy-3epi-dihydrocinchonine] its antipode and racemic analog;

7 trifiuoromethyl a(S) [5(8) ethyl 4(S)-quinuclidin-2(R)-yl]4-quinolinemethanol [hereinafter referred to as 7-trifiuoromethyl-3-epidihydrocincho-nine] its antipode and racemic analog.

Also included in the purview of the invention are compounds of the formulas wherein R is vinyl, methyl or C -C alkyl,

IId

their antipodes and racemates and pharmaceutically acceptable acid addition salts.

Also included in the purview of the invention are compounds of the formula:

The antipode of 6 methoxya(R)-[5(S)-ethyl-4(S)- quinuclidin-Z(S)-yl-4-quinolinemethano1 [hereinafter referred to as 6'-methoxy-3epi-dihydrocinchonidine or 3- epi-dihydroquinine] and its racemic analog (Compound A) and The antipode of 6 methoxy a(S)-[5(S)-ethyl-4(S)- quinuclidin-Z (R)-yl] 4-quinolinemethanol [hereinafter referred to as 6'-methoxy-3epi-dihydrocinchonine or 3-epidihydroquinidine] and its racemic analog (Compound B).

The compounds of Formulas Ic, Id, He and 11d, as well as Compounds A and B, are useful also as anti malarial and antiarrhythmic agents.

The compounds of the Formula IXa have demonstrated cardiovascular activity, such as, hypotensive activity. The pharmacologically useful cardiovascular activity is demonstrated in warm-blooded animals utilizing standard procedures. For example, the test compound is administered to anesthetized (30 mg./kg. sodium pentobarbital), artificially respired (Palmer Pump) dogs. Femoral arterial blood pressure and respiratory resistance (measured in terms of pressure) are recorded on a direct writing oscillographic recorder. A series of control responses of the blood pressure and respiration are obtained and duplicated. The control procedures used are: intravenously administered norepinephrine (1 /kg.), histamine (l 'y/kg.), serotonin (2S 'y/kg.) and hypertensin (0.5 'y/kg.), as well as the bilatrial occlusion of the carotid arteries and the electrical stimulation of the central portion of a severed vagus nerve (5 v., 50 c.p.s., sec). Each of the control procedures is administered at 5-minute intervals. Five minutes after the series of control responses, the drug to be tested is intravenously administered and its effects recorded. The series of control pro cedures is repeated after dosing to determine the effect of the compound on these standard responses. If the control responses are unaltered by the test drug, a second compound is administered and the procedure repeated. If the test compound alters the blood pressure or the control responses, the control procedures are repeated at 24 convenient intervals until the animal has returned to its predose status or a new physiological status is established. When meroquinenet-butylester d-monotartrate of the formula duneuotartrat-e is utilized as the test substance at a dose of 4 mg./kg. intravenously, the following results are obtained:

blood pressure: 25 for 35 minutes serotonin: N.E.

Central Vagus Stimulation: slight inhibition Carotid Occlusion: blocking Hypertension: N.E. Norepinephrine: slight inhibition Histamine: slight inhibition The compounds of Formula IXa also exhibit antiestrogenic activity. This useful estrogenic activity is demonstrated in warm-blooded animals. For example, the test compound is administered once daily for three consecutive days to groups of ten (10) immature female rats (-50 grams). On the first treatment day, all rats are injected subcutaneously with 0.25 meg. estradiol in sesame oil. On the fourth day, uteri are removed at autopsy and and weighed on a torsion balance.

When meroquinene-t-butylester d-monotartrate is utilized as the test substance at a dosage of l mg./kg. p.o., an 11 percent antiestrogen inhibition is observed with a 12 percent uterine change.

The compounds of Formulas Ia, Ila, Ib and Ilb, including compounds of the Formulas Ic, Id, IIc and 11d, as well as compounds A and B, and their pharmaceutically acceptable acid addition salts possess antimalarial and antiarrhythmic properties and are therefore useful as antimalarial and antiarrhythmic agents. Their pharmacologically useful antiarrhythmic activity is demonstrated in warm-blooded animals utilizing standard procedures, for example, the test compound is administered to prepared mongrel dogs. The chest cavity of the experimental animal previously anesthetized using a combination of sodium barbitol, 300 mg./kg. and pentobarbitol, 15 mg./ kg., i.e., is opened up through the third right interspace under artificial respiration and the pericardium is cut and sutured to the wall of the thorax so as to maintain the heart in a pericardial cradle throughout the course of the test procedures. Arterial pressure is monitored by inserting a polyethylene cannula into the aorta via the left carotid artery and is measured with an appropriate Statham pressure transducer. During the course of the experiment, electrical activity of the heart is viewed both on an oscilloscope and recorded on a Sanborn polyviso using standard ECG lead II. The heart is also observed visually. The antiarrhythmic assay of the test drug is undertaken using a modification of the method of Scherf o and Chick, 1951. A dripping of 1 percent solution of acetylcholine is applied to the sinus node and the atrium is irritated by pinch withing a pair of forceps. This procedure produces a continuous artiral arrhythmia which mostly consists of atrial fibrillation. Since hypokalemia a produces a susceptibility to atrial fibrillation (Leveque, 1964), 2 units/kg. of insulin is administered 30 minutes before the start of the acetylcholine drip. Once a trial fibrillation is established, there is a ten-minute waiting period before the test drug is administered. The test drugs are administered at the rate of 1 mgJ g /m te until normal sinus rhythm appears or until 30 mg./kg. of drug is administered.

When 6-ethoxy-a(R) [(R)-ethyl-4(S)-quinuc1idin- 2(S)-yl-4-quinoline methanol is utilized as the test substance at a dosage of about 4.0 mg./kg., an antifibrillatory effect is observed for more than 60 minutes.

Their pharmacological useful antimalarial activity is demonstrated in warm-blooded animals using standard procedures, for example, the test substance is adminis tered to albino mice in variable amounts. Albino mice are inoculated with about 5l0 million red cells infected with P. Bergei. Treatment is started on the first day after inoculation, and the drug is administered per os during 4 consecutive days. On the seventh day of infection, smears are made, stained with giemsa and microscopically examine for P. Bergei.

When racemic 7'-methoxy-dih'ydrocinchonidine dihydrochloride or racemic 7methoxy-dihydrocinchonine dihydrochloride is utilized as the test substance at dosages in the range of 125 mg./kg. to about 250 mg./l g., the microscopical examination of the blood smears is free of P. Berghei (negative). When 6'-methoxy-a(R)-[5(R)- ethyl-4(8)-quinuclidin-2(S) yl] 4 quinolinemethanol [dihydroquinine] or 6-methoxy-a(-R)-[5 (R)-ethyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol is utilized as the test substance at a dose of about 200 mg./kg., the microscopical examination of the blood smears is free of P. 'Berghei (negative). The compounds of Formulas Ia, Ha, Ib and 11b, including the compounds of Formulas Ic, Id, 11c and 11d, as well as compounds A and B, and their pharmaceutically acceptable acid addition salts have effects qualitatively similar, for example, to those of quinine and quinidine, known for their therapeutic uses and properties. Thus, the compounds of the invention demonstrate a pattern of activity associated with antimalarials and antiarrhythmics of known eflicacy and safety.

Furthermore, the compounds of the Formulas Ia, Ila, Ib and 11b, including the compounds of Formulas Ic, Id, He and 11d, as well as compounds A and B, can be utilized as flavoring agents in beverages in the same manner as quinine is now used for this purpose.

The compounds of Formulas Ia, IIa, Ib and 11b, including the compounds of Formulas Ic, Id, 110 and lld, as well as compounds A and B, form acid addition salts and such salts are also within the scope of this invention. Thus, the compounds of Formulas Ia, IIa, Ib and 11b, including the compounds of Formulas 10, Id, 11c and 11d, as well as compounds A and B, form pharmaceutically acceptable addition salts with, for example, both pharmaceutically acceptable addition salts with, for example, both pharmaceuticaly acceptable organic and inorganic acids, such as acetic acid, succinic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and the like.

The products of the invention can be incorporated into standard pharmaceutical dosage forms, for example, they are useful fororal or parenteral application with the usual pharmaceutical adjuvant materials, e.g., organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols, and the like. The pharmaceutical preparations can be employed in a solid form, e.g., as tablets, troches, suppositories, capsules, or in liquid form, e.g., as solutions, suspensions 0r emulsions. The pharmaceutical adjuvant material can include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. They can also contain other therapeutically active materials.

The quantity of active medicament which is present in any of the above-described dosage forms is variable. The frequency with which any such dosage form will be administered will vary, depending upon the quantity of active medicament present therein, and the needs and requirements of the pharmacological situation.

Due to'the possible differentspatial arrangements of their atoms, it is to be understood that the'compoii'nds of this invention may be obtained in more than one possible stereoisomeric form. The novel compounds, as described EXAMPLE 1 Preparation of racemic cis 2-benzoyl-octahydro-6(2H)- isoquinolone from racemic 2-benzoyl-1,3,4,7,8,8a-hexahydro-6 (2H) -isoquinolone To a solution containing 151 g. of racemic 2-benzoyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone in 3000 ml. of absolute ethanol were added 300 ml. of 3 N aqueous hydrochloric acid and 30 g. of 5% rhodium on alumina catalyst. The mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. The catalyst was removed by filtration and washed thoroughly with ethanol. The filtrate was partially evaporated in vacuo, diluted with 3500 ml. of dichloromethane and washed with 3 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and sodium chloride solutions. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to yield a crystalline product. Gas chromatographic analysis indicated that it contained 61.9% of racemic cis 2-benzoyl-octahydro-6(2H)-isoquinolone and 13% of racemic trans 2-benzoyl-octahydro-6(2H)-isoquinolone. The product was recrystallized twice from benzene to give racemic cis 2-benzoyl-octahydro-6(2H)-isoquinolone having a melting point of 147148.5.

EXAMPLE 2 Preparation of racemic trans 2-benzoyl-octahydro-6(2H)- isoquinolone from racemic 2-benzoy1-1,3,4,7,8,8a-hexahydro-6 2H) -isoquinolone To a solution containing 25.5 g. of racemic Z-benzoyll,3,4,7,8,8a-hexahydro-6(ZI-D-isoquinolone in 1000 ml. of ethanol were added 2.5 g. of 10% palladium on carbon catalyst and the mixture was hydrogenated at room temperature and 3 atmospheres pressure until the uptake of hydrogen ceased. The catalyst was removed by filtration and washed with 95% ethanol and dichloromethane. The filtrate was evaporated to dryness to yield an oil which crystallized on trituration with ether. The product was recrystallized twice from absolute ethanol to yield racemic trans 2-benzoyl-octahydro-6(2H)-isoquinolone, which after two additional recrystallizations from absolute ethanol, had a melting point of 157.5-l59.

EXAMPLE 3 Preparation of 2'-'benzoyl-4(R),5(R)-dimethyl-l',2',3',4',

4'a(S),7,8,8'a (S)-octahydrospiro[1,3-dioxolane 2,6- (5H) isoquinoline] and 2 benzoyl 4(R),5(R)- dimethyl l,2',3,4,4a(R),7',8',8'a(R) octahydrospiro[1,3-dioxolane-2,6(5'H) -i soquinoline] I Y, I To a solution containing 23.4 g. of rac. trans-2-benzoyloctahydro-6(lH)-isoquinolone in 2 l. of anhydrous benzene was added 2.24 g. of p-toluenesulfonic acid and 9.83 g. of ()-butane-2(R),3(R')-di0l. The resulting solution was refluxed for 3 hours and the water which formed was collected in a water separator. After the addition of 18 ml. of pyridine, the mixture was diluted to 4 l. with benzene, washed four times with ml. of water,

dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The last traces of pyridine were re moved by codi'stillation with toluene in vacuo. The- 6 hours reflux with distilled petroleum ether (b.p. 3060 O) insoluble part soluble part rccrystalllrecrystallization Zation from from ethanol-water ether 1:1

EXAMPLE 4 Preparation of 4a(S),8a(S)-2-benzoyloctahydro-6(2H)- isoquinolone A solution containing 2.5 g. of 2'-benzoyl-4(R),5(R)- dimethyl 1,2,3,4',4'a(S),7,8,8a(S) octahydrospiro- [1,3-dioxolane-2,6'(5'H)-isoquinoline] in 100 ml. of 70% acetic acid was heated at 100105 for 1.5 hours. The reaction mixture was evaporated in vacuo, diluted with 1 l. of benzene, washed with 100 ml. of 2 N aqueous sodium carbonate and three times with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield 2 g. of 4a(S),8a(S)-2-benzoyloctahydro- 6(2H)-isoquinolone, having a melting point of 151 153 (from absolute ethanol); [04],; 61.8 (c. 1.01, CHCl EXAMPLE Preparation of 4a (R 8a (R) -2-benzoyloctahydro- 6 2H -isoquinolone A solution containing 0.329 g. of 2'-benzoyl-4(R), 5(R)- dimethyl 1,2',3',4',4a(R),7,8,8a(R)octahydrospiro- [1,3-dioxolane-2,6'(5H)-isoquinoline] in 50 ml. of 70% acetic acid was heated at 100105 for 4 hours and 40 minutes. The reaction mixture was evaporated in vacuo diluted with 500 ml. of benzene, washed with 50 ml. of 2 N aqueous sodium carbonate and 3 times with 50 ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield 0.256 g. of 4a(R),8a(R)-2 benzoyl-octahydro-6(2H)-isoquinolone having a melting point of 151-153 (from absolute ethanol); [04] 62.60 (c. 1.005, CHClg).

EMMPLE 6 Preparation of racemic cis 7-benzoyl-decahydro-2-H- pyrido[3,4-d]-azepin-2-one from racemic cis Z-benzoyl- Loctahydro-6 (2H -isoquinolone To a suspension containing 20.6 g. of finely ground racemic cis 2-benzoyl-octahydro-6(2H)-isoquinolone in 800 g. of polyphosphoric acid were added 10.0 g. of sodium azide, and the mixture was stirred 16 hours at 55-60". After cooling at room temperature, the reaction mixture was poured onto crushed ice. The resulting solution was made alkaline with solid sodium carbonate at 0, .and was extracted thoroughly with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The oily residue crystallized on trituration with acetone. Fractional crystallization of the crystalline prodnot from acetone yielded cis 7-benzoyl-decahydro-2H- pyrido[3,4 d]azepiI1-2-one, which after one recrystallization from absolute ethanol and three recrystallizations from acetone had a melting point of 167-168.5.,

EXAMPLE 7 To a mixture containing 5.15 g. of trans Z-benzoyloctahydro-6(2H)-isoquinolone and 200 g. of polyphosphoric acid were added 2.5 g. of sodium azide and the reaction mixture was stirred at 55-60 for 16 hours. After cooling to room temperature, the polyphosphoric acid was hydrolyzed by addition of ice. The resulting solution was made alkaline with concentrated sodium carbonate solution and extracted thoroughly with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 5.45 g. of crystalline racemic trans 7-benzoyl-decahydro-2H-pyrido [3,4-d]azepin-2-one. After recrystallization from ethanol/ ether it had a melting point of 187-189".

EXAMPLE 8 Preparation of 5 a (S) ,9a S) -7-benzoyldecahydro-2H- pyrido[3,4-d] azepin-Z-one To a mixture of finely ground 2.57 g. of 4a(S),8a(S)-2- benzoyloctahydro-6(2H)-isoquinolone and g. of polyphosphoric acid was added 1.3 g. of sodium azide. The reaction mixture was stirred at 55 60 C. (bath) for 16 hours, cooled to room temperature and poured into ca. 380 g. of crushed ice. After the ice had melted, the resulting solution was made alkaline with 6 N aqueous sodium carbonate (370 ml.) and extracted 3 times with 300 ml. of methylene chloride. Methylene chloride extract was washed 3 times with 40 ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness, to give 2.72 g. of crystalline 5a(S),9a(S)-7-benzoyldecahydro- 2H-pyrido[3,4-d]azepin-2-one. From absolute ethanol it crystallized with one mole of ethanol, M.P. 200 203 C., 37.83 (c. 1.0547, CHCI on drying loses ethanol to give anhydrous form, M.P. 90-100.

EXAMPLE 9 Preparation of racemic 2-benzoyl-1,2,3,4,7,8,9,9a-octahydro 6H pyrido[3,4-d] azepin-6-one from racemic 2-benzoyl-1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone To a suspension containing 1.02 g. of finely ground racemic 2-benzoyl-l,3,4,7,8,8a-hexahydro-6(2H)isoquin olone in 40 g. of polyphosphoric acid was added 0.5 g. of sodium azide and the reaction mixture was stirred at for 30 minutes. After cooling to room temperature, ice was added. The resulting solution was made alkaline with saturated aqueous sodium carbonate at 0 and was extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The product was crystallized by trituration with acetone to give racemic 2 benzoyl 1,2,3,4,7,8,9,9a octahydro-6H-pyrido[3,4-d] azepin-fi-one having a melting point of 2l9221.

EXAMPLE 10 Preparation of racemic cis. 7-benzoyl-decahydro-2H- pyrido[3,4-d] azepin-Z-one from racemic 2-benzoyl-1,2, 3,4,7, 8,9,9a-octahydro-6H-pyrido 3,4-d] azepin-6-one uptake of hydrogen ceased. Thereafter, the catalyst was removed by filtration and washed thoroughly with ethanol. The filtrate was neutralized with 2 N aqueous sodium carbonate and evaporated to a small volume in vacuo. The residue was extracted with 1000 ml. of dichloromethane.

EXAMPLE 11 Preparation of racemic cis 1-benzoy1-3-(2-aminoethyl)-4- 'piperidineacetic acid ethyl ester from racemic cis 7-benzoyl-decahydro-2H-pyrido [3,4-d] azepin-Z-one A solution containing 2.8 g. of racemic cis 7-benzoyldecahydro 2H-pyrido[3,4-d]azepin-2-one in 5 ml. of ethanolic hydrochloric acid was refluxed for 100 hours. Thereafter, the solvent was removed by evaporation in vacuo. The residue was taken up in 1200 ml. of dichlorornethane. The resulting solution was shaken with a solution containing 0.53 g. of sodium carbonate in ml. of water, dried over anhydrous sodium sulfate and evaporatedto yield oily racemic cis l-benzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester.

EXAMPLE 12 Preparation of racemic trans 1-benzoyl-3-(2-aminoethyl)- 4-piperidineacetic acid ethyl ester from racemic trans 7-benzoyl-decahydro-ZH-pyrido [3 ,4-d] azepin-2-one EXAMPLE 13 Preparation of racemic cis l-benzoyl 3 vinyl-4-piperidineacetic acid ethyl ester (racemic N-benzoylmeroquinne ethyl ester) from racemic cis 1-benzoyl-3-(2- aminoethyl)-4-piperidineacetic acid ethyl ester A mixture containing 1.91 g. of racemic cis 1-benzoyl 3-(2-aminoethyl) 4 piperidineacetic acid ethyl ester, 1.38 g. of formic acid and 1.05 g. of 37% formaldehyde was heated for 1 hour at 100. After cooling to room temperature, 3.5 ml. of concentrated hydrochloric acid were added and the mixture thus obtained was evaporated to dryness in vacuo. The residue was dissolved in 50 :ml. of water. The solution was washed by shaking with ether, made alkaline to about a pH 8 with 2 N sodium carbonate and extracted thoroughly with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give oily racemic cis 1-benzoyl-3-(2-dimethylaminoethyl) 4 piperidineacetic acid ethyl ester. To the stirredv solution containing'this product in 10 ml. of

methanol were added 2 ml. of 30% aqueous hydrogen peroxide at 0. The reaction mixture was warmed to room temperature and stirred for 16 hours. The excess of hydrogen peroxide was decomposed by addition of platinum blackhwith stirring for 1 hour at 0. The platinum black was separated by filtration and washed withmethanol. "Ihe ffiltrate was evaporated to dryness in vacuo to yieldracemic cis 1-benzoyl-3-(2-dimethylaminoethyl) A piperidineacetic acid ethyl ester N- ozide, asair oil. Heating of this product in vacuo at a temperature from 90'? to. 125 C. over a period of 25 minutesyielded racemic .N-benzoylmeroquinene ethyl ester, which, after purification by preparative thin layer chromatography and recrystallization from hexane, had a melting point of 66-68.

3 0 EXAMPLE 14 Preparation of racemic trans 1-benzoyl-3-(2 dimethylaminoethyl) 4 piperidineacetic acid ethyl ester from racemic trans 1-benzoyl-3-(Z-aminoethyl)-4-piperidineacetic acid ethyl ester A mixture containing 1.4 g. of racemic trans l-benzoyl- 3-(2-aminoethyl) 4 piperidineacetic acid ethyl ester,

1.4 g. of formic acid and 1.1 g. of 37% aqueous formaldehyde was heated at 100. The reaction mixture became a clear solution and a vigorous evolution of gas occurred, which ceased after 1.5 hours. After cooling to room temperature, 1 ml. of concentrated hydrochloric acid was added and the mixture was evaporated in vacuo. The residue was dissolved in ml. of water, washed by shaking with ether, made alkaline with 2 N aqueous sodium carbonate and extracted thoroughly with dichloromethane. The extract was dried over anhydrous sodium sulfate and evaporated to yield racemic trans l-benzoyl- 3-(2 dirnethylaminoethyl) 4 piperidine acetic acid ethyl ester.

EXAMPLE 15 Preparation of racemic trans l-benzoyl 3 (Z-dimethylaminoethyl) 4 piperidineacetic acid ethyl ester N- oxide from racemic trans l-benzoyl 3 (Z-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester To a stirred solution containing 0.73 g. of racemic trans l-benzoyl 3 (Z-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester in 10 ml. of methanol was added 1 m1. of 30% hydrogen peroxide at 0. The reaction mixture was allowed to warm to room temperature and was then stirred overnight. The excess of hydrogen peroxide was decomposed by stirring with platinum black for 2 hours at 0 C. The platinum black was removed by filtration and the filtrate evaporated to dryness yielding racemic trans l-benzoyl 3 (2 dimethylaminoethyl)-4pi peridineacetic acid ethyl ester N-oxide.

EXAMPLE 16 Preparation of racemic trans l-benzoyl 3 vinyl-4-piperidineacetic acid ethyl ester from racemic trans 1- benzoyl 3 (Z-dimethylaminoethyl) 4 piperidineacetic acid ethyl ester N-oxide A flask containing 0.63 g. of racemic trans l-benzoyl- 3 (2 dirnethylaminoethyl) 4 piperidineacetic acid ethyl ester N-oxide was pyrolyzed at 90-l20 for 20 minutes. The product was chromatographed on a 400 g. silica gel column with ether to yield racemic trans 1- benz-oyl 3 vinyl 4 piperidineacetic acid ethyl ester as a glass.

EXAMPLE 17 Preparation of racemic cis 7-benzoyl 1 nitroso-decahydro 2H pyrido[3,4-d]azepin-2-one from racemic cis 7 benzoyl-decahydro-ZH-pyrido[3,4-d1azepin-2-one To a solution containing 5.521 g. of nitrogen tetroxide in 360 ml. of carbon tetrachloride at 70 were added 9.84- g. of anhydrous sodium acetate. The mixture was allowed to warm to 0 and a solution containing 10.88 g. of racemic cis 7 benzoyl-decahydro 2H pyrido- [3,4-d1azepin-2-one in 40 ml. of dichloromethane'was added with stirring. After 30 minutes.at 0, the mixture was poured into a slurry of ice and water. The resulting mixture was placed in a separatory funnel and the organic phase was separated. The aqueous phase was extractedthoroughly with ice-cold dichloromethane. The combined organic phases were washed with. water, dried over anhydrous sodium sulfate, and evaporated to dryness at 0 C. in vacuo to yield oily racemic cis 7-benzoyl-1- nitroso-deoahydro-2H-pyrido[3,4-d]azepin-2-one.

31 EXAMPLE 18 Preparation of racemic trans 7-benzoyl 1 nitroso-decahydro-2I-I pyrido[3,4d]azepin 2 one from racemic trans 7 benzoyl-decahydro-ZH-pyrido[3,4-d] azepin- 2-one To 100 ml. of carbontetrachloride solution containing 1.31 g. of nitrogentetroxide at 70 were added 2.46 g. of anhydrous sodium acetate. The mixture was allowed to warm to and 2.6 g. of racemic trans 7-benzoyl-decahydro 2H pyrido[3,4-d1azepin-2-one in 50 ml. of dichloromethane were added with stirring. The reaction mixture was maintained at 0 for 30 minutes. Thereafter, it was poured into a slurry of ice and water, transferred to a separatory funnel and the organic phase was removed. The aqueous phase was extracted with three 250 ml. portions of dichloromethane. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield racemic trans 7-benzoyl 1 nitroso-decahydro 2H pyrido- [3,4-d]azepin2-one, a green yellow powder. All operations were carried out at 0.

EXAMPLE 19 Preparation of racemic N-benzoyl-meroquinene [racemic cis l-benzoyl-3-vinyl-4-piperidineacetic acid] from racemic cis 7-benzoyl-1-nitroso-decahydro-2H-pyrido- [3,4-d]azepine-2-one The racemic cis 7-benzoyl-1-nitroso-decahydro-2H- pyrido-[3,2-d]azepine-Z-one from Example 17 was placed in a flask fitted with a reflux condenser and heated under nitrogen on an oil bath maintained at 125 for about 1 hour. The residue was taken up in 50 ml. of l N potassium hydroxide, diluted with 50 ml. of water and washed by shaking with ether. The aqueous phase was neutralized with 50 ml. of l N hydrochloric acid and extracted with ether. The ether phase was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to yield racemic N-benzoyl-meroquinene, as an oil.

EXAMPLE 20 Preparation of racemic trans l-benzoyl-3-vinyl-4-piperidineacetic acid from racemic trans 7-benzoyl-1-nitrosodecahydro-ZH-pyrido- 3,4-d] azepin-Z-one The product of Example 18, i.e., racemic trans 7-benzoyl-1-nitroso-decahydro-2H-pyrido [3 ,4-d] azepin-2-one was heated at 125 under nitrogen for 1 hour. The product was taken up in 13 ml. of 1 N aqueous potassium hydroxide and 30 ml. of water, washed with four 100 ml. portions of ether, neutralized with 13 ml. of l N aqueous hydrochloric acid and extracted with four 200 ml. portions of ether. The ethereal extract was washed with 70 ml. of water, which was combined with aqueous phase, dried over anhydrous magnesium sulfate and evaporated to yield oily racemic trans 1-benZoyl-3-vinyl-4-piperidineacetic acid.

EXAMPLE 21 Preparation of 1-benzoyl-3 (S)-vinyl-4(S)-piperidineacetic acid To 143 ml. of'0.15 M solution of dinitrogen tetroxide in carbontetrachloride immersed in a Dry Ice-acetone bath were added 3.51 g. of anhydrous sodium acetate, and the mixture was allowed to warm to 0 C. A solution containing' 3.86 g. of a(S),9a(S)-7-benzoyldecahydro-2I-I- pyrido[3,4-d]azepin-2-one in 50 ml. of methylene chloride was added with stirring, and after standing for 30 minutes at 0 C. the mixture was poured into a slurry of ice and water (280 ml.). The resulting mixture was placed in a separatory funnel and the organic phase was removed. The aqueous phase was extracted 3 times with 430 ml. of methylene chloride. The combined organic phases were washed with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo. All these operations were carried out at 0 C. It gave quantitative yield of pale yellow powder, l-nitroso-5a(S),9a(S)-7-benzoyldecahydro-ZH-pyrido[3,4-d1azepin 2 one, which was processed immediately further.

The nitroso product was heated at 125 C. (bath) under nitrogen. Initially violent reaction ceased slowly after 30 minutes. The residue (3.92 g.) was taken up in 19 ml. of 1 N aqueous potassium hydroxide, diluted with water (60 ml.) and washed 4 times with 150 ml. of ether. It was then neutralized with 19 ml. of l N aqueous hydrochloric acid and extracted 4 times with 300 ml. of ether.-The ethereal extract was washed with 60 ml. of water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 2.34 g. of oily 1-benzoyl-3(S)-vinyl-4(S)'- piperidineacetic acid which contained minor impurities (tLc). 7

EXAMPLE 22 Preparation of racemic N-benzoylmeroquinene methyl ester [racemic cis l-benZoyl-3-vinyl 4-piperidineacetic acid methyl ester] ,from racemic N-benzoylmeroquinene [racemic cis 1-benzoyl-3-vinyl-4-piperidineacetic acid] EXAMPLE 23 Preparation of 1 benzoyl 3(R)-vinyl-4(S)-piperidineacetaldehyde from l-benzoyl-3 (R) -vinyl-4 (S -piperidineacetic acid methyl ester To a Dry Ice cooled solution of 1.48 g. (0.005 mole) of 1-benzoyl-3 (R)-vinyl-4(S)-piperidineacetic acid methyl ester in 100 ml. of toluene was added dropwise (5 min.) with stirring 8 ml. (ca. 0.012 mole) of a 25% solution of diisobutyl aluminum hydride in toluene. Stirring was continued for 30 min. at 78, then 5 ml. of methanolwater 1:1) was added, and stirring at -78 was continued. After min., 0.6 ml. (0.005 mole) of benzoylchloride and 4 g. of solid sodium carbonate was added, the Dry Ice bath was removed, and the mixture was stirred for 60 min. The inorganic solids were removed by filtration, washed with methanol, and the combined organic phases evaporated to dryness. The crude product was dissolved in ml. of dichloromethane, washed l X l N sodium carbonate, 1 water), dried (sodium sulfate) and evaporated. The crude product (1.7 g.) was separated by preparative layer chromatography to give 0.235 'g. (17.5%) of 1-benzoyl-3(R)-vinyl-4(S)-piperidineacetaldehyde as a colorless oil. 1

EXAMPLE 24 To the solution of 0.476 g. of rac. trans l b enz oyl-3- vinyl-4-piperidineacetic acid in 4 ml. of methanol was added 9 ml. of diazomethane solution in ether (concentration ca. 3 g./ ml.). After few minutes an additional 9 ml. of diazomethane solution was added, and then stirred at room temperature for 1 hour. The excess of diazomethane was destroyed by addition of several drops glacial acetic acid, and thus resulted mixture was evaporated to dryness in vacuo, leaving 0.5 g. of oily residue. The crude product was chromatographed on 7 Brinkman silica gel preparative plates with benzene-ether 1:1 mixture. Elution with 95% ethanol gave 0.201 g. of oily rac. trans 1-benZoyl-3-vinyl-4-piperidineacetic acid' methyl ester.

33 EX P E Preparation of 1-benzoyl-3 (S)- vinyl-4(S)-piperidine- I acetic acid methyl ester 1 Y To a cooled solution containing 2.34 g. of l-benzoyl- 3(S)-vinyl-4(S)-pipe1idineacetic acid in 20 ml. of methanol was added 20 ml. of diazomethane solutiin in ether (concentration ca. 3 g./130 1111.). After few minutes an additional 20 ml. of diazomethane solution was added and then stirred at room temperature for 5 minutes. The excess of diazomethane was destroyed by addition of several drops of glacial acetic acid, and thus resulted mixture was evaporated to dryness in vacuo, leaving 2.9 g. of oily residue. The crude product was chromatographed on 26 Brinkman silica gel preparative plates with benzene-ether 1:1 mixture. Elution with 95% ethanol gave 1.059 g. of oily 1 benzoyl-3(S)-vinyl-4(S)-piperidineacetic acid methyl ester, [M 1.61 (c. 1.1193, CHCI EXAMPLE 26 Preparation of racernic 3-(a-benzyloxycarbonylcyanomethyl)glutaric acid diethyl ester To the boiling solution of 37.24 g. of glutaconic acid diethyl ester and 70.08 g. of benzylcyanoacetate in 100 ml. of anhydrous tetrahydrofuran was added dropwise 22.4 g. (0.20 mole) of potassium t-butoxide in 300 ml. of anhydrous tetrahydrofuran over a hour-hour period. The reaction mixture was stirred and refluxed for 12 hours. The solvent was removed by distillation in vacuo. To the residue was added 100 ml. of water and extracted with 3 1. of benzene. The benzene extract was washed four times with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was fractionally distilled to give 42.55 g. of racemic 3-(ocbenzyloxycarbonylcyanomethyl)glutaric acid diethyl ester, B.P. 167-174 at 0.15 mm. Hg. Large scale runs average to 61% yield.

EXAMPLE 27 Preparation of racernic 3-(1-benzyloxycarbony1-1- cyanopropyl)glutaric acid diethyl ester The mixture of 18 g. of racernic 3-(oa-b8I1ZYlOXYC3I- bonylcyanomethyl)g1utaric acid diethyl ester, 15.6 g. of ethyliodide and 6.72 g. of potassium t-butoxide in 200 ml. of anhydrous tetrahydrofuran was stirred and refluxed for 3 hours, which it became neutral. The precipitate formed during the reaction was separated by filtration and washed with tetrahydrofuran. The combined filtrates were evaporated to dryness, and after addition of 20 ml. of water, extracted with 1 1. of benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was fractionally distilled to give 11.35 g. of racernic 3 (l-benzyloxycarbonyl-l-cyanopropyDglutaric acid diethyl ester, B.P. 154159 at 25 microns. Large scale runs average to 70% yield.

EXAMPLE 28 Preparation of racernic 3-( 1-cyanopropyl)glutaric acid diethyl ester To the solution of 23.4 g. (0.06 mole) of ,3'-.(1-ben zy1- oxycarbonyl-l-cyanopropyl)glutaricacid diethyl ester in 600 ml. of 95% ethanol was added 3 g. of %pall'adiur'n on carbon, and hydrogenated atroom temperature and atmospheric pressure. After uptake of 0.06 mole of ydrogen, the reaction ceased. Catalyst was removed by filtration through celite, and the filtrate was evaporated to dryness. The residue, 2032 g., was heatedat 170 180 in vacuo for 1 hour. After cooling to roorntem; perature, it was dissolved in 1 l. of ether. The ethereal solution was washed'three times with 50 ml. of concentrated aqueous solution of sodiumbicarbonate, and water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 14.17 g. of racernic 3-(l-cyanopropyl) glutaric acid diethyl ester, B.P. 8486 at 20 microns.

EXAMPLE 29 Preparation of racernic cis 4 ethoxycarbonylmethyl-S- ethyl- 2-piperidone and racernic trans 4-ethoxycarbonylmethyl-S-ethyl-2-piperidone To a solution of 101.23 g. (0.395 mole) of 3-(1-cyanopropyl)glutaric acid diethyl ester in 1200 ml. of absolute ethanol was added 31.8 g. of Raney nickel, and hydrogenated at 110 atm and temperature, which in the course of three hours rose slowly from room to 152 C. After cooling to room temperature, the catalyst was separated by filtration through celite and the filtrate evaporated to dryness in vacuo. On trituration with ether, 57.6 g. of racernic trans 4 ethoxycarbonylmethyl-5-ethyl-2-piperidone, M.P. 86-88 was obtained. After one recrystallization from methylene chloride-ether, M.P. was 89- 91.

The mother liquors were evaporated to give 23.5 g. of oily residue, which was chromatographed on a 2 kg. silica gel column. The elution with ethanol-chloroform mixture gave 16 g. of racernic cis 4-ethoxycarbonylmethyl-5- ethyI-Z-piperidone.

EXAMPLE 30 Preparation of racernic trans 3-ethyl-4-piperidineacetic acid ethyl ester The solution of 0.640 g. of racernic trans 4-ethoxycarbonylmethyl-S-ethyl 2 piperidone and 0.684 g. of triethyloxonium fluoroborate in 20' ml. of anhydrous methylene chloride was stirred at room temperature hours, and then evaporated in vacuo. The crude enolether was dissolved in 20 ml. of absolute ethanol, the solution was cooled-to 0 C. and 0.25 g. (0.0066 mole) of sodium borohydride was added in portions. The reaction mixture was stirred for 23 hours at room temperature, then diluted with 50 ml. of water and extracted with 1 l. of methylene chloride. Methylene chloride extract was washed with water (3X 50 ml.), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in 7 m1. of ice-cold. 1 N hydrochloric acid, the resulting solution diluted with ml. of water and washed 5 times by shaking with 50 ml. of ether. It was then made alkaline with 8 ml. of 1 N sodium hydroxide and extracted with 1 1. of methylene chloride. Methylene chloride extract was washed three times with 50 ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness, to give 0.591 g. (99%) of racernic trans 3-ethyl-4-piperidineacetic acid ethyl ester B.P. 9l- 92 (bath) at 0.5 mm. Hg.

EXAMPLE 31 Preparation of racernic cis 6-methoxy-4-{3-[1-benzoyl-3- vinyl-4-piperidyl] 2 oxopropyl}quinoline from 6- met'hoxylepidine and racernic N-benzoylmeroquinene methyl ester [cis 1 benzoyl-3 -vinyl-4-piperidineacetic acid methyl ester] 1 ,To a solution containing about 0.032 mole of lithium diisopropyl amide .[prepared at 20 in an atmosphere of dry nitrogen bythe addition of 6 ml. of dry diisopropyl amine to. 15.5 ml. of phenyllithium in benzene-ether (7:3)]Qwereadded dropwise a solution containing 5.6 g. of 6 'mcthoxylepidinein 60 ml. of anhydrous tetrahydrofuran. The reaction mixture was stirred for 20 minutes.

, To the practically homogeneous, dark-brown solution of 6-methoxylepidyl lithium thus obtained was added dropwise overaperiod of 20 minutes a solution containing 4.6 g. of racernic N-benzoylmeroquinene methyl ester in 60 mlfof anhydrous tetrahydrofuran. After the addition was completed, stirring wascontinued for 60 minutes. During the whole operation the reaction temperature was maintained at 20. Thereafter, ice and water were added and the reaction mixture was neutralized to a pH 8 with acetic acid and 10% sodium bicarbonate. The aqueous phase was extracted thoroughly with ether. The ethereal extract was washed with water, dried over anhydrous magnesium sulfate and evaporated. The residuewas'adsorbed on a 550 g. neutral alumina column (activity 11). After elution of unreacted fi-methoxylepidine with benzene, the amorphous racemic cis-6-methoxy-4-{3-[l-benzoyl-3vinyl-4-piperidyl] 2 oxopropyl}quinoline was eluted with benzene containing 20-50% of ethyl acetate.

EXAMPLE 32 Preparation of 6-methoxy 4{3 [1-benzoyl-3 (R)-vinyl- 4(S)-piperidyl] 2 oxopropyl}quinoline from 6-methoxy-l-lepidine and N-benzoyl meroquinene ethyl ester To a solution of ca. 0.07 mole of lithium diisopropyl amide [prepared by addition of 15 ml. of dry diisopropyl amine in 10 ml. of toluene to 35 ml. of ca. 2 molar n-butyl lithium in hexane, at 78 under nitrogen] was added dropwise (10 min.) with stirring a solution of 13 g. (0.075 mole) of 6-methoxy-lepidine in 120 ml. of tetrahydrofuran. The mixture was stirred at 78 for 30 min., and there was added dropwise (10 min.) a solution of 10.5 g. (0.0345 mole) of N-benzoylmeroquinene ethyl ester in 150 ml. of tetrahydrofuran. Stirring was continued at 78 for 30 min. The cooling bath was removed and the stirring was continued for another 30 min. Water was added, the aqueous layer was neutralized (pH ca. 8) with acetic acid and extracted thoroughly with ether. The ethereal phase was washed (water), dried (magnesium sulfate) and evaporated in vacuo. The residue was absorbed on 600 g. of neutral alumina, activity II; after elution of excess 6-methoxy-lepidine with benzene, elution with benzene-ethyl acetate (1:1) afforded amorphous 6-methoxy- 4{3-[1-benzoyl-3 (R)-vinyl-4(S)-piperidyl] 2 oxopropyl}-quinoline; [a] +27.3 (c. 205; chloroform).

EXAMPLE 33 Preparation of 6 methoxy-4{3-[1-benzoyl-3(R)-vinyl- 4(S)-piperidyl] 2 oxopropyl}quinline from 6-methoxylepidine and N-benzoyl-meroquinene methyl ester A condensation reaction carried out in analogous way as in Example 30a with 1.8 g. (0.0104 mole) of 6-methoxylepidine and 1.49 g. (0.0052 mole) of N-benzoylmeroquinene methyl ester (phenyl lithium was used instead of n-butyl lithium) yielded after a similar technique and separation by column chromatography 6-methyl-4{3- [1-benzoyl-3(R)-vinyl-4(S)-piperidyl] 2 oxopropyl} quinoline.

EXAMPLE 34 Preparation of 7-chloro-4-{3-[ 1-benzoy1-3 (R)-vinyl-4(S)- piperidyl]-2-oXopropyl}-quin0line from 7 chlorolepidine and N-benzoyl-meroquinene ethyl ester To a Dry Ice cooled solution of ca. 0.061 mole of lithium diisopropyl amide [prepared in an atmosphere of dry nitrogen by addition of 10 ml. (ca. 0.07 mole) of diisopropylamine in 30 ml. of tetrahydrofuran to 30 ml; of

(a. 2 M n-butyllithium in hexane] was added-dropwise (2.0 min.) a solution of 11 g. (0.061 mole) of 7-chlorolepidine in 60 ml. of tetrahydrofuran. The resulting brown suspension was stirred at -78 for 30 min., then there was added. a solution of 9.2 g. (0.0305 mole) of N- benzoyl-meroquinene ethyl ester in 60 ml. of tetrahydrofuran. Stirring was continued at 78 for 40-min. After removing'the cooling bath, stirring was continued'for another 40 min. After addition of 50 ml. of 'waterg'the mixture was neutralized with acetic acid and the pHwas adjusted to ca. '8 by addition of 10%-sodium bicarbonate. The aqueous phase was extracted thoroughly'with -ether, the etherealphases were washed (2x 10% sodium bicarbonate), dried'(magnesium sulfate) and evaporated to dryness. Crystallization from acetone-ether alforded crysstalline 7 chloro-4-{3-[1 benzoyl-3 (R)-vinyl-4(S)-piperidyl]-2-oxopropyl}quinoline; the mother liquor was absorbed on 300- g. of neutral alumina, activity II, and elution with ethyl acetate afforded additional amounts of 7- chloro-4-{1-[1-benzoyl 3(R)-vinyl 4(S)-piperidyl]-2- oxopropyl}quinoline; M.P. 147148 (acetone); [(11 +387 (0. 1.00, chloroform).

EXAMPLE 35 Preparation of epimeric 7-ohloro-4-{3-[3 (R)-vinyl-4(S)- piperidyl]-2hydroxypropyl}-quinolines from 7-chloro- 4-{3-[1-benzoyl-3 (R)-vinyl-4(S)-piperidyl] 2 oxopropyl}quinoline To an ice cold solution of 7.84 g. (0.018 mole) of 7- chloro-4-{3-[1-benzoyl' 3(R) vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline in 200 ml. of methanol was added excess solid sodium borohydride, and the solution was stirred for 60 min. at 0. Fifty ml. of water was added, the methanol was evaporated in vacuo, and the aqueous residue was extracted thoroughly with dichloromethane. The organic extracts were washed (sat. sodium chloride); dried (sodium sulfate) and evaporated to give epimeric 2-hydroxypropyl}quinolines. The crude, dried product was dissolved in 200 ml. of dry toluene and 50 ml. of dry tetrahydrofuran, the solution was cooled to 78, and 25 ml. (ca. 0.04 mole) of a 25% solution of diisobutyl aluminum hydride in toluene was added dropwise (15 min.) The homogeneous solution was stirred at 78 for 40 min., 60 ml. of methanol-water (1:1) was added, and stirring was continued for 20 min. at 78, then for 2 hrs. without cooling. The inorganic precipitate was removed by filtration and washed thoroughly with methanol. The combined filtrates were evaporated to dryness and the residue was partitioned between ether and 1 N hydrochloric acid. The acidic extracts were made alkaline (conc. ammonia) and extracted thoroughly with dichloromethane. The organic phase was washed (sat. sodium chloride), dried (sodium sulfate) and evaporated to give amorphous epimeric 7-chloro 4 {3-[3 (R)-vinyl-4(S piperidyl]2-hydroxypropyl}quinolines.

EXAMPLE 3 6 Racemic trans 6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)- 2-oxopropyl] quinoline from 6,8-dimethoxy lepidine and racemic trans 3-ethyl-4-piperidineacetic acid ethyl ester To a Dry Ice cooled solution of ca. 0.036 mole of lithium diisopropyl amide (prepared by addition of 6 ml. of diisopropyl amine in 10 ml. of toluene to 16 ml. of ca. 2 M n-butyl lithium in hexane, at 78 in an atmosphere of dry nitrogen) was added dropwise (5 min.) with stirring a solution of 7.3 g. (0.036 mole) of 6,8-dimemethoxy-lepidine in 50 ml. of dry tetrahydrofuran. The inhomogeneous mixture containing 6,8-dimethoxy lepidyl lithium was stirred for 15 min., then a solution of 3.65 g. (0.018 mole) of trans 3-ethyl 4"- piperidineacetic acid ethylester in50 ml. of tetrahydrofuran was added dropwise (30 min.). Stirring was continued for 60 min. at 78". 50 ml. of water was added, the aqueous phase was neutralized with acetic acid (pH ca. 8) and extracted thoroughly withether. The ethereal phase was washed (ca. 1% sodium bicarbonate solution), dried (sodium sulfate), and evaporated to give a crude product (ca 6 g.), containing only traces of ketone 4' as indicated by thin layer "chromatography. The combined aqueous phases were 's'atu'rated with sodium chloride and extracted thoroughly with chloroform-ethanol (19:1), the organic extracts were dried (sodium sulfate) and evaporated in vacuo to give 5 g. (ca. of practicallypure racemic trans "6,8 dimethoxy 4 [3-(3-ethyl-4-piperidyl)2-oxopropyl] quinoline as a yellow oil.

EXAMPLE 37 To a solution containing about 0.034 mole of lithium diisopropyl amide.[prepared at 80 in an atmosphere of dry nitrogen by addition of 6 ml. of dry diisopropylamine to 16 ml. of about 2.14 molar phenyllithium in benzeneether (7:3)] was added dropwise a solution containing 6 g. of 6-methoxylepidine in about 25 ml. of anhydrous tetrahydrofuran and the reaction mixture was stirred at :for .20 minutes. To the practically homogeneous, darkbrown solution of 6-methoxylepidyl lithium thus obtained, was added dropwise a solution containing 3.5 g. of meroquinene ethyl ester in 40 ml. of dry tetrahydrofuran with stirring at 0 for 60 minutesn-After the addition of 50 ml. of water, the reaction mixture was neutralized with acetic acid sodium acetate to pI-Iz9 and extracted thoroughly with ether. The. ethereal extract was washed with water, driedover anhydrous magnesiumsulfate and evaporated. The residue was absorbed on a 350 g. neutral alumina column (activity II) after elution of unreacted 6-methoxylepidine with dichloromethane, amorphous 6-methoxy- 4;,{3- [3 R) -vinyl-4 (S -piperidyl] -2 -oxopropyl} quinoline was eluted with ,dichloromethane containing 1 to of methanol. 1 r EXAMPLE 38 Preparation of 7 chloro 4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl} quinoline from 7-chlorolepidine and meroquinene ethyl ester [3(R) vinyl-4(S)-piperidineacetic acid ethyl ester] To a solution containing about 0.0075 mole of lithium diisopropylamide [prepared in an atmosphere of dry nitro genbyaddition of 1.3 ml. of dry diisopropylamine in 4 m1. of anhydrous tetrahydrofuran to 3.5 ml. of about 2.1 molar phenyllithium in benzene-ether (7:3)], cooled on a Dry Ice bath, was added dropwise with stirring a solution containing 1.33 g. of dry 7-chlorolepidine in 30 ml. of anhydrous tetrahydrofuran. The reaction mixture was stirred at 75 for 20. minutes. To the stirred, practically homogeneous, reddish-brown solution of 7-chlorolepidyl lithium thus obtained, was added dropwise a solution containing 0.70 g. of dry meroquinene ethyl ester in ml. of anhydrous tetrahydrofuran. The dry-ice bath was removed and the solution was stirred at --75 to +20 for 3 hours. After the addition of 10 ml. of water, the reaction mixture was neutralized (pH about 8) by addition of acetic acid and 10% sodium bicarbonate, and extracted thoroughly with ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue, a yellow oil, was adsorbed on a 70 g. neutral alumina (activity II) column. After elution of unreacted 7-chlorolepidine with 'dichloromethane, yellow amorphous 7 chloro-4-(3-[3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl} quinoline was eluted with dichloromethane containing 2 to 10% of methanol. The monohydrochlo'ride of 7-chloro-4-{3-[3 (R) -vinyl-4(S) -piperidyl]- 2-oxopropyl} quinoline was recrystallized from methanolacetone having a melting point of 236-237 (dec.), 11, +269", (c.,1.02 CH OH).

EXAMPLE39 Preparation, of epimeric G-methoxy 4,- {3-[-3(R)-vinyl- 4(S) -piperidyl]-2-hydroxypropyl} quiuolines from recernic cis 6-methoxy-4-(3-[1-benzoyl-3-vinyl-4-piperidyl]- XOPI PY q lin I 1 v r To a stirred solution containing 2.8 g. of racemiccis oxopropyl}-quin0line'in150ml. of dry toluene'at 0, was" added dropwisea solutioncontaining 25% diisobutyl aluminum hydride in toluene, while the course ofthe reaction was checked by tLc. After 12 ml. were added, the reaction was quenched by the addition of 10 ml. of an ice coldmixture of water-methanol (I1 :1). The resulting mixture was stirred at 20. The alumina which precipitated was then removed by filtration, washed thoroughly with methanol, and the combined filtrates were evaporated to dryness. The residue was dissolved in dichloromethane, washed With 1 N sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated. The product, racemic epimaric cis '6-methoxy-4-{3-[3-vinyl-4-piperidyl]-2-hydroxypropyl} quinolines was dissolved in 40 ml. of acetone, and added to the solution containing 1 g. of dibenzoyl-(d)-tartaric acid in 10 ml. of methanol. Crystallization yielded the corresponding dibenzoyl- (d)-tartrate. The mother liquor was converted to the free base which was purified by filtration on a 20 g. neutral alumina column (activity 11). Elution with dichloromethane-methanol (9:1) gave additional product which could not be crystallized as. the neutral dibenzoyl-(d)- tartrate.

To complete resolution, the above-mentioned crystalline dibenzoyl-(d)-tartrate was recrystallized 4 times from methanolacetone to give the neutral dibenzoyl-(d) tartrates of the epimeric 6-methoxy-4-{3-[3(R)-vinyl- 4(S)-piperidyl]-2-hydroxypropyl}quinolines having a melting point of 189-190"; [a] =-27.4 (c. 0.82, methanol).

EXAMPLE 40 Racemic, epimeric trans6,8-dimethoxy-4-[3-(3-ethyl-4- piperidyl)-3-hydroxypropyl]quinolines from racemic trans 6,8-dimethoxy-4-[3 (3-ethyl-4-piperidyl)-2-oxopropyl] quinoline To a stirred, ice cold solution of '5 g. (0.014 mole) of racemic trans6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)- 2-oxopropyl] quinoline in ml. of methanol was added 0.9 g. of solid sodium borohydride. After stirring for 60 min., 50 ml. of water was added and the methanol was removed by evaporation. The aqueous residue was saturated with sodium chloride and extracted thoroughly with chloroform-ethanol (9:1). The extracts were dried (sodium sulfate) and evaporated to give 5 g. (quantitative recovery) of racemic, epimeric trans6,8- .dimethoxy-4-[3-(3-ethyl-4 piperidyl)-2-hydroxypropyl] quinolines as a crude oil.

EXAMPLE 41 Preparation of epimeric 6-methoxy-4-{3-[3(R)-vinyl- 4(S)-piperidyl]-2-hydroxypropyl}quinolines from 6- methoxy-4-{3-[3(R)-vinyl 4(S) piperidyl]-2-oxopropyl}quinoline A solution containing 1.8 g. of 6-methoxy-4-{3-[3(R)- vinyl-4(S)-piperidyl]-2-oxopropyl}quinoline in 20 m1. of methanol was added to an ice cold solution containing 1 g. of sodium borohydride in 100 ml. of methanol. The solution was stirred at 0 to 20 for 90 minutes. After addition of 50 ml. of water, the methanol was removed by distillation. The remaining aqueous phase was extracted with dichloromethane. The extract was washed with 1 N aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue wasdissolv'ed in a small"'volume of methanol, and added toa solution containing 0.98 g; of dibenzoyl-(d)-tartafic"acid in acetone. Crystallization yielded theneutral;-dibenzoylfld.) -tar trates of the epimeric t 9'Xy- 3.rtflt l nyl-fls)-p p r dy 1=2- h r x w i q ins v n am inspq f H5 190 after recrystallization}, from methanol qetone; [a] -=27.0 (c. 1.09, methanol).

EXAMPLE 42 Preparation of e imeric 7-chloro-4-{3-[3(R)-vinyl-4(S)- piperidyl]-2-hydroxypropyl}quinolines from 7-chloro- 4-{3-[3 (R) -vinyl-4(S) piperidyl] -2-oxopropyl} quinoline To a stirred, ice cold solution containing 1.98 g. of

7-chloro-4-{3-[3(R)-vinyl 4(S) piperidyl]-2-oxopropyl}quinoline in 60 m1. of methanol was added 1 g.

of sodium borohydride in portions. After stirring for minutes, ml. of water were added and the methanol was evaporated. The remaining mixture was made alkaline with 1 N sodium hydroxide and extracted thoroughly with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to yield 1.61 g. of epimeric 7-chloro-4-{3- [3(R)-vinyl-4(S)-piperidyl] 2 hydroxypropyl}quinolines. The neutral dibenzoyl-(d)-tartrate had a melting point of 198-199" after recrystallization from dichloromethanemethanol.

EXAMPLE 43 Preparation of epimeric 6-methoxy-4-{3-[1-benzoyl-3(R)- vinyl-4(S)-piperidyl] 2 hydroxypropyl}quinolines from 6-methoxylepidine and 1-benzoyl-3 (R)-'vinyl- 4 (S) -piperidineacetaldehyde To ca. 0.0055 mole of lithium diisopropyl amide [prepared in an atmosphere of dry nitrogen by addition of 0.8 ml. (ca. 0.06 mole) of diisopropyl amine to 2.6 ml. of 2.14 M phenyl lithium in hexane] was added with stirring a solution of .95 g. (0.0055 mole) of -methoxylepidine in 7 ml. of benzene and ml. of tetrahydrofuran. After stirring at room temperature for 20 minutes a solution of 0.95 g. (0.0037 mole) of 1-benzoyl-3(R)- vinyl-4(S)-piperidineacetaldehyde in 14 ml. of tetrahydrofuran was added dropwise min.), and the resulting mixture was stirred at room temperature for 15 hours. Water (50 ml.) was added, the aqueous phase was extracted thoroughly with ether. The ethereal phase was washed (2 aq. sodium chloride), dried (sodium sulfate) and evaporated to dryness. The crude product (2.4 g.) was absorbed on 100 g. of neutral alumina, activity II, and elution with ethyl acetate containing 1% of methanol aiforded 0.88 g. (55%) of epimeric 6-methoxy-4-{3- l-benzoyl 3 (R)-vinyl-4(S) -piperidyl]- Z-hydroxypropyl}quinolines as a colorless oil.

EXAMPLE 44 Preparation of epimeric 6-methoxy-4-{3-[3(R)-vinyl- 4(S)-piperidyl]-2-hydroxypropyl}quinolines from epimeric 6-methoxy-4-{3-[l benzoyl 3(R)-vinyl-4(S)- piperidyl]-2-hydroxypropyl}quinolines lines.

Preparation. of epimeric 6-methoxy-4-{ 3- 3 (R) -vinyl- "4(S)*piperidyl]-2-acetoxypropyl}quinoline' from -ep i'- To a. solution containing 1.15 g. of epimeric 6-methoxy- 4,-{3-[3 (R) vinyl- 4(S)- p iperidyl] 2 hydroxypropyl} quinolines in 40 ml. of glacial acetic acid were added 4 ml. of freshly distilled borontrifiuoride etherate. The solu- 40 tion was kept at 50 for 18 hours. Thereafter, the reaction mixture was concentrated in vacuo to about 10 ml., and, after addition of ice, neutralized (pH ca. 8) with 6 N sodium hydroxide. The ice cold, alkaline phase was extracted thoroughly with dichloromethane, and the extracts were washed with water, dried over anhydroussodium sulfate and evaporated to yield epimeric 6-methoxy-4-{3- [3(R) vinyl-4(S)-piperidyl]-'2-acetoxypropyl}quinolines as colorless glass; [04 f+21.4 (c. 0.835, chloroform).

EXAMPLE 46 Racemic, epimeric trans6,8-dimethoxy-4-[3-(3-ethyl-4- piperidyl)-2-acetoxypr0pyl]quinolines from racemic, epimeric trans6,8-dimethoxy-4- 3- (3-ethyl-4-piperidyl) 2-hydroxypropyl]-quinolines To a solution of a crude mixture of 5 g. (ca. 0.014 mole) of racemic, epimeric trans6,8-dimethoXy-4-[3-(3- ethyl-4piperidyl)-2-hydroxypropyl] quinolines in'200 ml. of glacial acetic acid was added 20 ml. of highly distilled borontrifiuoride etherate, and the' solution was kept at 50 for 15 hours. The acetic acid was stripped off, ice-water was added, the aqueous solution was neutralized with conc. ammonium hydroxide to pH ca. 8 and extracted thoroughly with dichloromethane. The organic extracts were washed (saturated sodium chloride), dried (sodium sulfate)v and evaporated to dryness to give 4.5 g. (ca. percent) of racemic, epimeric trans6,8-dimethoxy-4-[3- (3-ethyl-4-piperidyl)-2-acetoxypropyl] .quinolines' as a crude oil. 7

EXAMPLE 47' Preparation of epimeric 7-chlor0-4-{3-[3(R)-vinyl-4 (S)- piperidyl]-2-acetoxypropyl}quinolines from epimeric 7 chloro-4-{3( [3(R) (vinyl-4(S)-piperidyl} 2 hydroxypropyl] quinolines To a solution containing 0.656 g. of epimeric 7-chloro- 4-{3-[3(R)-vinyl-4(S) piperidyl] 2 hydroxypropyl} quinolines in 30 ml. of glacial acetic acid were added 3 ml. of freshly distilled borontrifiuoride etherate. The solution was kept at 50 for 19 hours. Thereafter, the reaction mixture was concentrated in vacuo to about 10 ml. Ice was added and the ice cold mixture was neutralized (pH ca. 8) with 6 N sodium hydroxide and thoroughly extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography [chloroform-triethylamine (9:1)] to yield epimeric 7-chloro-4-{3-[3(R)- vinyl-4(S)-piperidyl]-2-acetoxypropyl}quinolines as a viscous oil.

EXAMPLE 48 Preparation of cis and trans 6-methOXy-4-{3-[3(R)-vinyl- 4(R)-piperidyl]prop-1-enyl}quinolines from epimeric 6-methoxy-4-{3-[3 (R) -.viny1 4(S) piperidyl]-Z-hyroxypropyl}quinolines To an ice cold solution containing 0.6 g. of epimeric 6 methoxy 4 {3 [3(R) vinyl 4(S) piperidyl]- Z-hydroxypropyl}quinolines in 20 ml. of pyridine was added 1.0 ml. of thionylchloride. The resulting reddishbrown solution was kept at 0 to 20;? for 4 hours. Water was 'added and the aqueous phase was neutralized with acetic acid to a pHz7 and extracted thoroughly with dichloromethane. The organic extracts were washed with water, dried over anhydrous sodium sulfate and evapora'ted'to yield amorphous mixture of cis and, trans 6,-methoxy-4-{3-[3(R) vinyl 4(R)-piperidyl]-pr'op-1-enyl} quinolines. i I a 

